The role of the ATM gene in breast cancer predisposition is controversial. Studies of carriers of ATM mutations have indicated that females have on average a 4-7 fold increased risk of breast cancer, but mutation analysis of the ATM gene in unselected breast cancer cases has failed to find a convincingly increased frequency compared with controls. However, we have shown that two specific pathogenic mutations of the ATM gene do occur in 4% of multiple-case breast cancer families, and confer high risks of breast cancer, equivalent to a risk to age 70 years of 60%. The broad aim of this proposal is to extend our finding by estimating the penetrance and frequency of breast cancer-causing ATM mutations by analysis of the gene in almost 3000 putative hereditary breast cancer families from North America and Australia. Our specific aims are to: 1) Perform mutation screening of ATM in the youngest affected female from 900 breast cancer families. 2) Identify putative ATM mutations among the variants found by analyses of the behaviour of these variants in tumors and cell lines from women who carry them. 3) Screen 2000 additional breast cancer families for putative ATM mutations defined in Aim 2. 4) Genotype the affected and unaffected family members of those individuals found to carry putative ATM mutations, and estimate the penetrance of these mutations. 5) Estimate the frequency of ATM mutations in defined groups of unselected population-based breast cancer cases. Our findings will have numerous clinical implications, including whether women in high-risk families should be routinely or selectively screened for ATM, as well as BRCA1 and BRCA2 mutations. In addition, knowledge of ATM mutation status will allow future assessment of many clinical issues, including genetic and environmental modifiers of penetrance, appropriate surveillance, disease severity, patients' response to different treatment regimens, and possible adverse reactions to radiotherapy. The results of this research may directly affect treatment decisions, and improve preventive monitoring in high-risk families. [unreadable] [unreadable]